Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels

Which FT3, FT4 and TSH levels have the highest and lowest prevalence rates for 10 common health disorders?

  1. Hypertension
  2. Hyperlipidemia (high cholesterol)
  3. Depression
  4. Diabetes
  5. Coronary artery disease
  6. Heart failure
  7. Atrial fibrillation
  8. Peripheral vascular disease
  9. Renal failure (kidney failure)
  10. Dementia

Is high-normal TSH and low FT3 associated with one condition, while high-normal FT4 and low or high TSH strongly associated with another condition?

Or do they all have a generally similar pattern of strong disease associations with certain thyroid hormone levels?

Anderson et al, 2020 collected data from the medical charts of 174,914 adults from 1999 to 2018 and associated their diagnoses at the time of their FT4, TSH, and FT3 thyroid laboratory tests.

The researchers provided this rich treasure trove of data in appendix tables. However, their article focused only on atrial fibrillation risk and singled out the FT4 hormone because of their chosen data analysis methods.

Here I bring Anderson and team’s appendix data set into focus through visual and verbal analyses their article had no time or space to provide.

In the 10 data tables, the visual patterns will jump out through heat maps that color-code higher and lower prevalence rates in a grid of 18 hormone categories (6 levels per hormone x 3 hormones).

Each disease’s table comes with a scientific discussion of its puzzles and patterns that you can click to expand. Read quotations from other scientists that noticed similar patterns and commented on them.

At the end, tables summarize rankings of prevalence rates: One gives the average rank of prevalence rates across all 10 disorders and the other focuses on 4 cardiovascular disorders.

What can we learn from this comparison?

  • Normal TSH levels rarely associated with the lowest rates of these disorders, which is unexpected given prevailing beliefs about the safety of normal TSH.
  • Abnormally high or low TSH categories rarely had the highest prevalence rates for these disorders, which is also unexpected for the same reason.
  • Instead, FT4 and FT3 levels usually had the highest and lowest prevalence rates.
  • TSH and FT4 levels in high-normal range often had higher prevalence rates than extremely high or low levels, which is puzzling.
  • FT3 and FT4 prevalence rates often trended in the opposite direction from each other. This shows that the human body responds differently to these two forms of thyroid hormone in circulation.
  • Hormone categories with lower average FT3:FT4 ratios often correlated with higher disease prevalence rates. Therefore, the hormone relationships matter, not just their levels.

Why has it been so difficult for scientists and doctors to see these patterns emerge in disease prevalence rates? What are the implications of long term medical blindness to the power of FT3 levels and FT3:FT4 ratios in human health? What do the data mean for treated thyroid patients? I’ll give some suggestions for action.

Copyright fair dealing note

Quotation, paraphrase, and reproduction, annotation, and adaptation of graphs and tables from copyrighted scientific publications is acceptable within the terms of Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info

How did Anderson and team obtain their data?

In a health care region in the northwestern United States, medical records between 1999 and 2018 were searched.

  • Adults over 18 years old, 174,914 were chosen if they had a FT4 lab test and were not treated with thyroid medications. The date of this FT4 test was considered their “study entry” date.
  • Among these people, 147,834 had a TSH test within 60 days of their study entry.
  • Among these people, 26,524 also had a FT3 test within 60 days.

On average, people had one, two, or three of these these tests within a period of only 2 days.

The population’s official diagnostic codes for atrial fibrillation and 9 other chronic diseases at the time of this set of tests were recorded. Therefore, the research team tabulated disease association rates with each subcategory of hormone levels.

Anderson’s article, titled “Free thyroxine within the normal reference range predicts
risk of atrial fibrillation,”
focused on one disorder — atrial fibrillation (AF).

See our article that focuses only on the atrial fibrillation (AF) data set.

Why are these unadjusted prevalence rates worthy of analysis?

For advanced scientific readers: Click to expand

While the prevalence data set is rich and interesting, Anderson and team’s analysis methods to adjust for confounding variables and to calculate hazard ratios (risk) relied on problematic assumptions and procedures critiqued in other medical research literature.

In short, Anderson and team only looked for linear trends within reference that were unique for atrial fibrillation.

They then found that high-normal FT4 fit the narrow pattern they were looking for within the narrow range they were interested in.

Their method of analysis ignored the stronger, non-linear U-shaped patterns of prevalence rates in FT3 and TSH, as if only “linear trends” matter for human health. In some cases, like thyroid hormones, the very same health disorder may occur at both higher and lower concentrations of hormone. It is well known that various types of cardiovascular disease occur in both extremes of hyperthyroidism and hypothyroidism (Zhang et al, 2019). This parallel risk at both ends of a spectrum creates a “U-shaped” pattern of risk on a line graph.

Anderson’s methods of adjustment also incorporated an “overadjustment bias” by unnecessarily adjusting for the prevalence rates of too many other cardiovascular conditions (presumably the many conditions in their appendix tables) that, like AF, also had strong disease associations with low FT3 and high-normal TSH.

Anderson and team also deemphasized FT4 and FT3 hormone levels beyond the reference range (despite a large percentage of their population having values beyond their laboratory’s ranges). This choice made them ignore the higher rates for AF in the High FT4 and Low FT3 categories. The human body does not monitor laboratory reference ranges and treat them as barriers. One or another hormone may go above or below the statistical normal range during illness. Research must see what nature really does and then use the natural patterns to create groups of data for analysis.

Therefore, looking at their raw, unadjusted, and unanalyzed data set is better than looking through the lens of their biased analytical procedures.

There’s so much to learn from the diverse data in their appendix. It’s a treasure-hoard of rich data that show patterns that map onto emerging research on TSH, FT4, and FT3 in various diseases.

For more information about their methods, consult their original article available in full online. See my basic critique in our blog post introducing their main unadjusted data set, “Anderson, 2020: Thyroid hormones and atrial fibrillation“.

How to read Anderson’s data

In the tables below, each hormone has six levels from low to high:

  1. Low,
  2. Normal Q1,
  3. Normal Q2,
  4. Normal Q3,
  5. Normal Q4,
  6. High

The four divisions within in reference range are “quartiles.”

The reference ranges were:

  • FT4: 0.75 to 1.50 ng/dL
  • TSH: 0.54 to 6.80 mcIU/L (Units equal to mU/L; 0.4 to 4.0 is more common.)
  • FT3: 2.40 to 4.20 pg/mL (100x smaller than the usual unit for FT3, pg/dL)

Where do the 4 Quartiles fit within reference range?

Anderson and team put all the people with “Normal FT4” and divided them into four equal sized groups, and did the same for the other two data sets. Dividing data into (3) tertiles, (4) quartiles or (5) quintiles is standard practice.

This resulted in each group covering a different portion of each reference range.

  • Notice the pink gridlines representing the reference ranges for the hormones.
  • Notice the size of Q4 on the right hand side of the diagram. Anderson’s “Normal Q4” quartile encompassed most or all of the upper half of reference range for each hormone. Q1, Q2, and Q3 cover narrower regions in the lower half of the reference ranges.

The TSH upper limit is controversial. In the region of the US where the study was conducted, the TSH limit was raised significantly near the very end of the study period. Their “Normal Q4” includes TSH values up to 6.80 mIU/L. (See “Details on methods” below). This means that some people with subclinical hypothyroidism were misclassified in Normal Q4.

Caution: These data are only from people on NO thyroid therapy.

The following prevalence rates are associations found in UNtreated individuals.

These associations cannot translate to simple prescriptions for treated thyroid patients’ hormone levels.

Thyroid disease and its treatments distort TSH-FT4-FT3 hormone relationships.

The prevalence rates you see below will be different in various populations of treated thyroid patients on different thyroid hormone treatments — levothyroxine (LT4), liothyronine (LT3), porcine desiccated thyroid, and combinations.

There is no simple way to prevent risk in a hormone-treated person whose FT3:FT4 ratio is abnormal and TSH-FT3 relationship is abnormal during thyroid therapy. In some patients, the HPT axis is untrustworthy, and TSH is lower than it should be per unit of FT4 and FT3 because of dysfunctional TSH secretion.

Therefore, chronic disease prevalence research, risk assessment and therapy decisions must be approached with great caution and respect for adaptation to individual thyroid disabilities.

The 10 chronic disorders

1. Hypertension

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]

Hypertension prevalence rates: Discussion
49.2%Average rate across all hormone levels
% below averageCategory% above averageCategory
-0.5%High FT45.5%FT4 Normal Q4
2.4%TSH Normal Q2 9.9%High TSH
-13.9%High FT33.1%Low FT4
Hypertension data analysis

In this population NOT treated with thyroid hormones,

  • High TSH (>6.80 mU/L) had the highest prevalence rate of hypertension, 59.1%.
    • These people would be diagnosed either with subclinical hypothyroidism (if TSH >10 but FT4 “normal”) or overt hypothyroidism (if low FT4, especially if TSH >10).
  • High FT3 with overt hyperthyroidism and a high FT3:FT4 ratio had the lowest prevalence rate for hypertension, 35.3%.

Puzzles and patterns

1. Low FT3 is not the highest prevalence rate. This is unusual considering the patterns that show up in this list below. It suggests that in this disorder, lack of T3 signaling is worsened by a high TSH. Therefore, scientists should consider the independent role of TSH receptor signaling on the cardiovascular system.

2. Low TSH versus High FT3. The cohorts in these two categories share a low average TSH. Why is the prevalence rate 18.5% higher for hypertension in the Low TSH category? Notice that in the Low TSH category:

  • the FT3:FT4 ratio is not as high,
  • the FT4 is significantly higher than all quartiles of FT3 in the normal range, and that FT4 in Normal Q4 has an almost equal rate.
  • Between these two hormone level categories, the shared feature of the average low TSH is not as significant as the two thyroid hormones.

These findings may appear paradoxical to some people because hypertension (high blood pressure) is usually associated with a low heart rate, and lower heart rate is associated with hypothyroidism. Yet hypothyroidism had the highest prevalence rate for hypertension!

However, “thyroid & cardiology” experts know about this association.

Stabouli et al (2010) write:

Hypothyroidism has been recognized as a cause of secondary hypertension.

Previous studies on the prevalence of hypertension in subjects with hypothyroidism have demonstrated elevated blood pressure values.”

In their section on “Mechanisms of Hypothyroidism-related Hypertension,” Stabouli and team explain:

“3,5,3′-triiodothyronine [T3 hormone] represents the metabolically active thyroid agent that possibly has a vasodilatory effect on the vascular muscle cells.”

Dilating blood vessels relaxes them. That’s what T3 does.

On the other end of the spectrum, the lower FT3 end,

Hypothyroidism and T3 deficiency are associated with peripheral vasoconstriction. 

DII [D2, deiodinase type 2] was identified in cultured human coronary and aortic arterial smooth muscle cells.

DII is believed to be responsible for the local conversion of T4 to T3 in these vessels.”

In addition, Stabouli et al explain that low T3 levels can lead to renal (kidney) dysfunction (see “Renal Failure” rates below). Kidney disorders can affect blood pressure and lead to other cardiovascular problems.

Low T3 hypothyroidism can cause dysfunction with the renin–angiotensin–aldosterone system (RAAS), which “is important for medium- and long-term BP regulation.” (Stabouli et al, 2010)

A few more patterns…

3. U-shaped (or J-shaped) pattern in TSH levels. The rate is lowest in Q2. Rates of hypertension are significantly worse in High TSH than low.

4. Rising linear trend in FT4 levels until High FT4. The higher the FT4, the higher the prevalence rate for hypertension. However, the higher FT3:FT4 ratio in the High FT4 category breaks the trend.

5. Falling linear trend in FT3 levels. The higher the FT3, the lower the prevalence rate for hypertension.

2. Hyperlipidemia

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Hyperlipidemia prevalence rates: Discussion
48.2%Average prevalence rate across all hormone levels
% below averageCategory  % above averageCategory
-6.3%High FT43.4%FT4 in Normal Q2
-5.3%High TSH6.1%TSH in Normal Q2
-9.6%High FT30.2%FT3 in Normal Q1
Hyperlipidemia data analysis

In this population NOT treated with thyroid hormones,

  • TSH in Normal Q2 (1.31‐2.04 mU/L) had the highest prevalence rate of high cholesterol, 54.3%.
    • There was not much difference among three TSH levels in normal range. They all had high prevalence rates.
    • Normal TSH does not seem to be protective.
  • High FT3 with overt hyperthyroidism and a high FT3:FT4 ratio had the lowest prevalence rate for hyperlipidemia, 38.6%.

Puzzles and patterns

The high prevalence in the middle of the TSH reference range, which is unlike any other association pattern found among the 10 disorders listed here.

It also seems contradictory to find high prevalence rates here when “Subclinical hypothyroidism is known to be associated with increased serum cholesterol.” (Moreno-Navarrete et al, 2017)

However, in Anderson’s study, the TSH in Normal Q4 went up to 6.80 mIU/L, which offers a clue as to why this category had a high prevalence rate. Many patients with subclinical hypothyroidism were designated subclinical hypo prior to the significant rise in the upper TSH range boundary in 2017.

FT3 signaling offers a more significant clue to this puzzle.

  • Overall, with one exception (the Highest TSH category, which had a low FT3), high cholesterol seemed to be less prevalent when FT3 was higher.
  • Even the form of overt hypothyroidism with the highest FT3 (in the Low FT4 category, with a FT3 well in reference range), had a relatively low rate of hyperlipidemia.
  • None of the normal-range TSH categories had a FT3 higher than 23% of reference range, limiting the mere presence of “Normal TSH” from having an effect on lowering cholesterol.

T3 signaling reduces cholesterol

When Martin et al, 2017 analyzed Total T3 as a continuous variable, they found a linear inverse relationship between T3 and cholesterol throughout and beyond the T3 reference range:

“For each doubling in T3, non-HDL-C [cholesterol] was lower by 18.0 mg/dL (95% CI: 15.2 to 20.8; P < 0.001) and LDL-C [cholesterol] by 18.7 mg/dL (95% CI: 16.2 to 21.2; P < 0.001).”

As explained by Mullur et al, 2014, T3 hormone powerfully reduces the rate of cholesterol synthesis through multiple signaling pathways.

TSH signaling raises cholesterol

In contrast with the relationship of high T3 [and FT3] to low cholesterol, TSH signaling raises cholesterol:

“A positive association between serum thyroid-stimulating hormone (TSH) levels and atherogenic lipid profile, including total cholesterol, LDL cholesterol, and fasting triglyceride levels, is well known”

Moreno-Navarrete et al, 2017

In short, the TSH receptor, when activated, can powerfully drive up cholesterol biosynthesis in the liver.

Q: Why then did the high TSH category, the form of overt hypothyroidism with low FT3 and the highest TSH, have low prevalence for hyperlipidemia?

I would like to propose something not considered by cardiovascular researchers. TSH receptor signaling can be blocked in autoimmune hypothyroidism.

TSH receptor-blocking antibodies may limit cholesterol escalation despite a lower FT3 and higher TSH.

An unknown portion of subjects in the extreme high TSH category may have had TSH-receptor blocking antibodies (TBAb), which some studies have found in up to 46% of Atrophic Thyroiditis patients (a form of autoimmune hypothyroidism previously designated “primary myxedema” and “agoitrous” or “nongoitrous” hypothyroidism), and up to 36% of Hashimoto’s Thyroiditis patients (Diana et al, 2019).

These TBAb have the opposite effect of Graves’ disease antibodies at the TSH receptor. When these antibodies bind to the TSH receptor, instead of enhancing the TSH receptor signal, they block it to a level below even the constitutive signaling of an empty TSH receptor, as shown by McLachlan and Rapoport in 2013:

“The TSHR, similar to many receptors, has a degree of ligand-independent or constitutive activity […].

TSHR ligands (TSH or TSAb) further increase receptor activity […].

An inverse agonist [such as TBAb] suppresses constitutive activity [of the TSH receptor].”

It has long been known that “thyroid-blocking antibodies (TBAbs) have been shown to exhibit inverse agonist properties at TSHR” (Neumann et al, 2010). They block the TSH-receptor signal.

Here’s the paradox. Patients with TBAb activity can have an extremely high TSH level, 80 – 500 mIU/L. However, even a high amount of TSH hormone circulating in blood is unable to activate its blocked receptors in the thyroid gland and throughout the body. This blockage of the TSH-receptor signal and the resulting cAMP signal in cells lowers the FT3:FT4 ratio by downregulating the two main deiodinases that convert T4 to T3. Low levels of T3 in the pituitary gland also drive up TSH secretion very high, but it’s ineffectual TSH.

As the TBAb antibody not only blocks but inverts the TSHR signal, circulating TSH cannot enhance cholesterol synthesis in the liver.

The blocking antibody, which is rarely tested in clinical practice, may explain an apparent paradox: Some people with subclinical hypothyroidism (likely without the TBAb antibody with a mildly elevated TSH) can have a higher cholesterol than patients with overt hypothyroidism and excessively high TSH.

One really has to ask not just “how much TSH is in circulation” but “how much TSH-receptor signaling is possible, given the person’s antibody levels?

3. Depression

[T[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Depression prevalence rates: Discussion
25.3%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
-8.1%High FT42.5%Low FT4
-5.7%High TSH2.8%TSH in Normal Q2
-3.5%High FT35.3%Low FT3
Depression data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for depression, 30.6%.
    • Normal TSH does not seem to be protective.
    • Normal FT3 is not protective unless there is a high FT3:FT4 ratio.
  • High FT4 had the lowest prevalence rate for depression, 17.2%.

Both High FT3 and High FT4 seem to be helpful in depression.

Strangely, only one type of hypothyroidism has a low rate of depression: the one with the highest TSH.

Puzzles and patterns

The concentration of blue in the upper-right corner of the heat map and concentration of pink in the opposite corner is a pattern not seen in the other 9 disorders discussed here.

T3 treatment in psychiatry: The extremely high association of depression with Low FT3 makes one consider this may be one reason why T3 hormone therapy has often been pursued as a way of treating depression that is resistant to common depression medications. In a recent review, it was reported that

“T3 may increase serotonergic neurotransmission and has been studied as an add-on agent in patients with unipolar depression with and without thyroid dysfunction to accelerate, enhance, and augment the effects of tricyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs].”

Morin, 2015

Only one type of hyperthyroidism was more associated with depression: Subclinical hyperthyroidism with high-normal thyroid hormones.

The other two types of hyperthyroidism were different because thyroid hormones were abnormally high.

The lower rates of depression with higher FT4 contradicts many mainstream and alternative medicine teachings about avoiding high FT4.

If high FT4 is harmful for cardiovascular health but beneficial for depression, a healthy compromise may be found by increasing the FT3 instead of the FT4, and most certainly, by avoiding a low FT3.

Why does the highest TSH category associate so poorly with depression, compared with the Low FT4 category? That is the most puzzling pattern of all. Their prevalence rates are almost opposite.

  • Here’s one clue — the FT4 is significantly higher in the High TSH category, and in general, FT4 seems to give a linear pattern of association.

The way the brain metabolizes thyroid hormones

According to Mohácsik et al, 2011,

“a significant amount of brain T3 is derived from the local activation of prohormone T4 to T3 (80% in the cortex), suggesting that most T3 acting in the brain is generated in situ from T4 deiodination.

Normally, the brain depends more on T4 converting locally to T3, and it depends relatively less on Free T3 being transported into the brain. This could explain why FT4 is so important to the brain.

The brain predominantly expresses two deiodinases for conversion: D2 and D3. (This is different from other organs like the thyroid, the organ that expresses the most D1 and D2, with hardly any D3.)

The brain plays a sort of internal game of football between glial cells and neurons as explained by Mohácsik and team:.

“D2 is expressed in glial cells” […]

So the glial cells convert T4 to T3.

“D3 expression in the brain is restricted to neurons”

So, the neurons get rid of any excess T4 and T3 by converting T4 to RT3 and T3 to T2.

In this way, they cooperate:

glial D2 provides T3 for neighboring neurons that express TR [thyroid receptors] but lack T3 generating capacity”

Glial cells donate T3 to the neurons, and the FT3 that is sent off to neurons mixes with other FT3 in brain circulation.

The neurons have the thyroid receptors in them, but they can’t make their own local T3, so they have to depend on T3 donations 1) by T4-T3 conversion in glial cells, and 2) from FT3 crossing the blood-brain-barrier via MCT8 transporter.

The neurons also have to protect their receptors from being flooded by excess T3, so they are equipped with D3 to clear out any excess T4 and T3 that enter their cells.

Free T3 is still important!

Even though FT4 is the major source of hormone, the brain still needs Free T3 to top up locally generated T4-T3 conversion supply.

Being equipped with the ability to get rid of excess hormone (D3 has no known limit to its upregulation), the brain does far better with a slight excess of T3 than with a deficiency of FT3 crossing the BBB on transporters like MCT8.

If there is not enough locally-generated T3, and not enough peripheral FT3 entering brain to make up for the shortfall, the brain will become hypothyroid. This explains the high rate of prevalence for depression in the Low FT3 category.

FT3 becomes even more important if a person has a genetic polymorphism in their DIO2 gene. Jo et al, 2019 say

“Thr92Ala-DIO2 carriers do not produce sufficient amounts of T3 via D2.”

However, this usually becomes a bigger problem when the thyroid gland loses function and people are on T4 thyroid therapy:

“carriers of the Thr92Ala-DIO2 polymorphism are reportedly asymptomatic when surveyed through quality of life or thyroid-specific questionnaires.

“A phenotype has only been reported in connection with diagnosis and treatment for hypothyroidism”

It’s at this point that the brain feels the lower-than-average Free T3 levels commonly found in T4-monotherapy treated hypothyroidism ADDED to the even lower FT3 levels caused by a weaker D2 enzyme in glial cells!

Jo and team point out that

“the approximately 10% lower serum T3 levels observed in adequately LT4-treated hypothyroid patients could be the key element that tips the balance toward behavioral and cognitive dysfunction.”

The brain is used to having that FT3 floating around to top up the rate of local T4-T3 conversion, but now even the rate of local conversion is lower. It’s a double handicap.

Therefore, treatment with some T3 hormone makes sense in carriers, according to Jo et al, 2019:

” it would seem logical to explore further the sensible use of LT3 when treating hypothyroid carriers of the Thr92Ala-DIO2 polymorphism.” 

4. Diabetes

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Diabetes prevalence rates: Discussion
18.9%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
0.0%Low FT44.1%FT4 in Normal Q4
-0.4%High TSH2.8%TSH in Normal Q3 and Q4
-7.5%High FT34.4%Low FT3
Diabetes data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for diabetes, 23.3%.
    • Normal TSH does not seem to be protective.
  • High FT3 had the lowest prevalence rate for diabetes, 11.4%.
    • Normal FT3 is increasingly protective as it rises.

Puzzles and patterns

TSH is almost irrelevant for this disorder, as one can see only light shades of pink and blue in the line of TSH levels. FT3 and FT4 carry the emphasis for low and high prevalence rates.

  • Among the three types of hyperthyroidism seen in the dat set, only subclinical hyper is more associated with diabetes. The other two types of overt hyper had low diabetes rates.
  • Paradoxically, overt hypothyroidism, is not associated with high rates of diabetes. Only “tissue hypothyroidism” is associated because it is characterized by low T3.

The contrast is stark between FT4 in Normal Q4 and low FT3, with an almost similar rate of prevalence (23% vs 23.3%).

Instead, T3 and TSH have complex relationships to diabetes, as explained by Zhang et al, 2018:

  • T3 signaling enhances gluconeogenesis in liver. Metformin (diabetes medication) hinders gluconeogenesis in liver.
  • “TSH is also associated with hyperinsulinemia and insulin resistance.”

However, T3 signaling can also aid diabetes:

“T3 potentiated insulin signaling, improved insulin sensitivity, and increased insulin synthesis, which may contribute to its anti-diabetic effects. These findings may provide new approaches to the treatment of type 2 diabetes.”

[Lin et al, 2011]

It seems that this disorder shifts FT3:FT4 hormone ratios in ways that can worsen diabetes, creating a vicious cycle of low T3 signaling in tissues:

“T2DM reduces thyroid-stimulating hormone levels and impairs the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissues.

[Kalra et al, 2019]

In addition, an isolated low FT3 is associated with diabetic nephropathy. A recent study found that

“Of the 421 patients, 203 (48.2%) suffered from DN, and no difference was found between males and females. The patients with DN yielded significantly lower FT3 levels than those without DN (P < 0.01). The prevalence of DN showed a significantly decreasing trend across the three tertiles based on FT3 levels (59.6%, 46.4%, and 38.6%, P < 0.01).”

Wu et al, 2015

It is clear that one can’t assume that “high thyroid hormones” are always a bad thing for diabetes — one must specify whether FT3 or FT4 is high, because one is relatively benign while the other is less so, and their ratio matters.

Clearly, more study is needed that examines the FT3:FT4 ratio, not just isolated FT3 levels and FT4 levels and diabetes.

5. Coronary artery disease (CAD)

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
CAD prevalence rates: Discussion
16.4%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
-0.5%High FT42.2%FT4 in Normal Q4
0.4%TSH in Normal Q25.5%TSH in Normal Q4
-7.0%High FT34.1%Low FT3
Coronary artery disease – data analysis

In this population NOT treated with thyroid hormones,

  • TSH in Normal Q4 had the highest prevalence rate for CAD, 21.9%.
    • Normal TSH does not seem to be protective.
  • High FT3 had the lowest prevalence rate for CAD, 9.4%.
    • Normal FT3 is increasingly protective as it rises.

Puzzles and patterns

None of the FT4 levels seemed to matter. They are all faintly pastel when color-coded by Microsoft Excel. High FT4 had a mildly lower rate of prevalence.

TSH only had one major “hot spot” for CAD prevalence, and it was hidden within reference in Normal Q4, not likely to be flagged by a blood test result.

Low vs. higher FT3 seems to act as a clear on/off switch for CAD.

The results and conclusions of a recent study underline the importance of FT3 for CAD even within the context of “euthyroid” TSH and FT4 levels:

Single vessel disease was found in 23%, double vessel disease in 15% and triple vessel disease in 17% of patients. TSH and FT4 levels were also comparable between the groups.

Normal coronary group had significantly higher mean FT3 values than triple vessel disease (p=0.004) and FT3 levels showed an inverse relation with Gensini score (Pearson’s correlation =- 0.30) (p =0.002).

A level of FT3 ≤ 2.7 predicted the severity of CAD with a 70% sensitivity and 60% specificity (area under curve (AUC): 0.755, p=0.001).

In the absence of primary thyroid disease and acute coronary syndrome, the occurrence of CAD is associated with lower serum levels of FT3.

FT3 and not the FT4 and TSH levels may be used as an indicator of increased risk for severe CAD.

The present study clearly shows the existence of a strong association between the reduction of biologically active T3 and severity of coronary artery disease.

However, low T3 state could be at first interpreted as just a biological risk factor of severe coronary artery disease; only the demonstration of beneficial effects on cardiovascular, end points of long term T3 replacement in CAD patients with low T3 state can answer this fundamental issue.

Daswani et al, 2015

Fortunately, scientists, a lot of treated thyroid patients have CAD and are maintained on T4 monotherapy. You can try changing their thyroid therapy by including T3 hormone. Some of them will likely be happy to consent to participate, especially if they currently have low FT3:FT4 ratios. Keep them on this therapy for many years with their consent instead of just doing a short-term trial. Check up on them 3 years and 5 years and 10 years later to see how incorporating T3 has changed their health outcomes.

Even more fortunately, a lot of thyroid patients are already on long-term T3-T4 synthetic combination therapy or desiccated thyroid therapy. Recruit them. Study their prevalence rates for CAD today. You don’t have to wait 3-10 years to find out what T3 therapy did for this treated population’s prevalence rates for CAD. You can compare them with the rates of CAD in age- and sex-matched thyroid patients maintained on T4 monotherapy who have a similar thyroid diagnosis (i.e. total thyroidectomy). Cheaper study.

6. Heart failure

[TH = Thyroid hormones FT3 and FT4][See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Heart failure prevalence rates: Discussion
10.5%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
0.1%FT4 in Normal Q23.1%FT4 in Normal Q4
-1.1%TSH in Normal Q25.0%TSH in Normal Q4
-6.5%FT3 in Normal Q46.1%Low FT3
Heart failure data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for heart failure, 16.6%.
    • TSH in Normal Q4 had the second highest HF rate.
  • FT3 in Normal Q4 had the lowest prevalence rate for heart failure, 4.0%.
    • Normal FT3 appears to be protective as it rises from Q1 to Normal Q4.

Puzzles and patterns

In this disorder, the “on-off” switch of Low FT3 vs. high normal FT3 is also clear.

We also now have a U-shaped pattern appear in FT4 and TSH levels, with the high and low levels being more associated with heart failure than the lower half of reference range.

Two types of “overt hyper” — with different FT3:FT4 ratios — had very different prevalence rates for HF: 13.4% for a lower ratio, and 5.6% for a higher ratio.

Of relevance here is Pingitore’s clinical trial of T3 therapy in heart failure patients who do not have a thyroid disorder diagnosis:

“Our main finding was that L-T3 infusion induced a positive cardiac and neuroendocrine resetting characterized by improved SV of the left ventricle and deactivation of the neuroendocrine profile, resulting from the significant reduction in vasoconstrictor/sodium retaining noradrenaline, aldosterone, and in the counterpart NT-proBNP plasma levels. […]

Further evidence in favor of an indirect positive effect of T3 on neuroendocrine resetting is the observation of a decreased HR [heart rate].

Pingitore et al, 2008

Kishi et al, 2015 put their main conclusion into their article’s title:

Free triiodothyronine [FT3], not thyroid stimulating hormone [TSH], should be focused on for risk stratification in acute decompensated heart failure”

7. Atrial fibrillation

[[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Atrial fibrillation (AF) prevalence rates: Discussion
9.7%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-1.0%FT4 in Normal Q24.7%High FT4
-1.3%TSH in Normal Q24.0%TSH in Normal Q4
-5.8%FT3 in Normal Q45.9%Low FT3
Atrial fibrillation data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for AF, 15.6%.
    • Normal TSH does not seem to be protective.
    • FT4 levels also have high prevalence rates in the upper range.
  • Normal Q4 FT3 had the lowest prevalence rate for AF, 3.9%.
    • Normal FT3 is increasingly protective as it rises to Q4
    • This contrasts with the FT4 hormone as it rises to Q4, and also rises in prevalence rate.
    • The rate of AF in FT4 in Q4 is 3x the rate found in FT3 in Q4.

Puzzles and patterns

Notice that for AF, the risk jumps from 3.6% to 7.9% between high-normal and high FT3. Why does the risk almost double? And why is this type of hyperthyroidism less risky than the High FT4 category?

  • Notice that the high FT3 category has a high average FT4 alongside it, and the FT3 is the highest on the chart given the Ratio of average FT3:FT4 being 0.50.

Another set of researchers has noticed that FT3 is the most significant variable in atrial fibrillation.

An item not cited in Anderson’s 2020 article is Wei et al’s 2018 study titled:

“U-shaped association between serum free triiodothyronine [FT3] and recurrence of atrial fibrillation after catheter ablation”

Instead of studying AF prevalence or incidence, they studied AF recurrence in 1115 AF patients who underwent catheter ablation procedure.

Their baseline FT3, FT4 and TSH measures were wisely collected before the catheter ablation procedure, before they could not be influenced by Low T3 syndrome induced by surgery. They then analyzed these baseline values in light of AF recurrence after surgery, and the follow up period averaged 723 days (almost 2 years).

Not everyone had a recurrent episode of AF. Only 47.2% did. And thyroid hormones made a difference. Low FT3 made the biggest difference, followed by high FT3, and high-normal FT4 was next in line.

Only 9.8% of patients had a low FT3 and 1.2% had a high FT3 above laboratory reference range, which was 3.8 to 6.0 pmol/L. After dividing the FT3 data into 5 equal groups, the quintile 1 cutoff was 4.07 and quintile 5 cutoff was 5.10.

In the lowest-risk quintile 3 for FT3, Wei’s population had

  • a FT3 of 4.58 pmol/L (35% of the laboratory reference range) [This proves they were not a healthy cohort, since a strong mid-range tendency is found in a healthy population’s average (Ganslmeier et al, 2014)],
  • a FT4 of 11.61 pmol/L (57% of reference), and
  • a TSH of 1.82 mIU/L (28% of reference).

They concluded this:

“A non-linear, U-shaped association was observed between the FT3 categories and arrhythmia recurrence, and both high and low FT3 levels were associated with AF recurrence after catheter ablation.

Regarding FT4, only a high-normal level was found to be associated with AF recurrence after catheter ablation.

No association was found between the normal range of TSH levels and AF recurrence after the procedure.”

Their findings fit with Anderson’s regarding the FT4 and TSH.

Their findings do not fit with Anderson’s regarding the risk of high FT3 levels, but it’s important to offer caution to people who already have AF about how to prevent its recurrence after treatment.

It would have helped to use the FT3:FT4 ratio (which they did not calculate) to distinguish among those with a high FT3 who were more at risk of AF recurrence due to having a high-normal FT4 at the same time as a FT3 in their 5th quintile.

I will leave Wei with the final words on the dangers of lower-normal FT3 and low FT3:

“An intriguing and novel finding was that the lowest quintile of FT3 also related to arrhythmia recurrence (HR = 1.60, 95%CI, 1.26 to 2.03, P < 0.01).

Compared to patients with FT3 levels in the normal range, a low FT3 state was an independent predictor of arrhythmia recurrence after multivariable adjustment (HR = 1.56, 95% CI, 1.23 to 1.97, P < 0.01).”

Wei et al, 2018

8. Peripheral vascular disease (PVD)

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
PVD prevalence rates: Discussion
9.8%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-0.7%High FT41.0%Low FT4 or FT4 in Normal Q3 
0.2%TSH in Normal Q22.2%TSH in Normal Q4
-4.5%High FT33.9%Low FT3

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for PVD [peripheral vascular disease], 13.7%.
    • Normal TSH in Q4 is the next highest rate at 12%.
    • FT4 levels also have high prevalence rates in the upper range.
  • High FT3 had the lowest prevalence rate for PVD, 3.9%.
    • High FT4 had a slightly lower-than-average prevalence rate of 9.1%.

Puzzles and patterns

Wang et al, 2017 found a strong association between peripheral artery disease and both FT3 and the FT3:FT4 ratio:

“The prevalence of PAD decreased according to FT3 quartiles (5.0%, 2.7%, 2.4%, and 1.5%, respectively; P for trend < 0.0001)

and according to the FT3/FT4 ratio quartiles (4.8%, 3.1%, 2.2%, and 1.3%, respectively; P for trend < 0.0001)


higher serum FT3 levels within the normal range and increased FT3/FT4 ratio were significantly associated with a decreased risk of prevalence of PAD.

They say no significance with TSH or FT4, but there is a bit of a U shaped risk in their graphs.

9. Renal failure

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Renal failure prevalence rates: Discussion
6.6%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-1.2%High FT43.2%Low FT4
-0.7%TSH in Normal Q22.7%Low TSH
-4.7%FT3 in Normal Q48.1%Low FT3
Renal failure data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for renal failure, 14.7%.
    • No other hormone level category came near the high prevalence rate for Low FT3.
  • High-normal FT3 in Q4 had the lowest prevalence rate for renal failure, 1.9%.
    • No other hormone level category came near the low prevalence rates for higher levels of FT3

Puzzles and patterns

It appears that for kidney health, the FT3 concentration is an on/off switch.

Long ago, it was discovered that rat Kidney and Liver depended mainly on circulating FT3 to fill their T3 receptors in cells (Silva et al, 1978). These organs depend to a very limited degree on local T4-T3 conversion to meet their T3 receptor occupancy needs. The kidney needs adequate circulating FT3 more than it needs normal FT4.

Iglesias et al, 2017 in a research review titled “Thyroid dysfunction and kidney disease: an update” associate Low T3 with cardiac risk and inflammation in renal failure. They conclude by recommending FT3 testing:

Low T3 has been associated to different inflammation markers, endothelial activation, malnutrition, and cardiac dysfunction in CKD [chronic kidney disease]. […]

The role of T4 and TSH on morbidity and mortality in renal patients is less defined than T3 […]

Variations in both TSH and FT4 within the normal range appear not to have pathological significance. TSH and FT4 did not affect CVD [cardiovascular disease] and mortality in euthyroid PD [peritoneal dialysis] patients [147].

From these results it seems reasonable to perform a regular assessment of TFT [thyroid function tests] measuring mainly T3, and preferably FT3, for helping estimate the clinical outcome and mortality risk in dialysis population.”

10. Dementia

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Dementia prevalence rates: Discussion
1.8%Average prevalence rate across all hormone levels
% below averageCategoryHighest (% difference from average)
-0.1%High FT40.6%Low FT4
-0.1%TSH in Normal Q20.9%TSH in Normal Q4
-1.4%High FT31.0%Low FT3
Dementia data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for dementia, 2.8%.
    • A close second-place is awarded to high-normal TSH in Q4.
  • High FT3 had the lowest prevalence rate for dementia, 0.4%.
    • No level of TSH or FT4 came close to the reduced rates of prevalence found in higher levels of FT3.

Puzzles and patterns

As it does for renal failure, FT3 appears to control the on-off switch for dementia. And in dementia, upper-normal TSH is also to be avoided.

All three types of hypothyroidism had high rates of prevalence.

There appears to be a mild U-shaped risk relationship with TSH having the lowest prevalence rates in the Q2 of normal range. However, the lowest prevalence rates for TSH pale in comparison to the far lower rates in the normal and upper FT3 levels.

Strangely enough, High FT4 had a mildly below average prevalence rate of 1.7%, but high-normal FT4 and subclinical hyperthyroidism had rates of 2.3%.

Too many publications tout the normalcy of a mildly elevated TSH in the elderly and accept the inevitability of a lower FT3 in aging, a stage of life when dementia is more likely to occur.

Many studies on dementia treat it as part of Alzheimer’s disease.

Quinlan and team in 2019 wrote an article announcing in its title that “Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer’s disease.” Their major headings also proclaim what they found:

“Serum TSH and FT4 are not associated with the risk of dementia”

“Serum FT3 is associated with increased risk of conversion to AD [Alzheimer’s Disease]”

The details were as follows:

“Higher serum FT3 was associated with lower risk of conversion to AD [hazard ratio (HR) = 054; 95% confidence interval (CI): 0.32–0.92 per 1 pmol/L increase].

Furthermore, patients in the lowest serum FT3 quartile had a twofold increased risk of AD compared to those in the highest quartile (HR = 2.63; 95% CI: 1.06–6.47).”

However, the study focused on “predictive role of TH [thyroid hormone] in the early disease stages,” so unfortunately “In this study, participants were excluded due to … manifest dementia (n = 206)” Unsurprisingly, with this exclusion of people with dementia, “Serum concentrations of TSH, FT4, and FT3 did not associate with all-cause dementia or VaD [Vascular Dementia].”

Ranking summaries

For each of the 10 disorders, the 18 hormone level categories were ranked from lowest (1) to highest per set, using repeated numbers (5,5,5) when the prevalence rates were identical in two hormone level categories. This was the result:

The boldest colors are in the bottom row. FT3 spans an average prevalence rate ranking from 13.8 to 2.2. The difference between Low FT3 and Normal Q1 FT3 is almost double.

Beyond FT3, the secondary hot spot is TSH in Normal Q4, and the secondary cold spot is High FT4.

Narrowing down the ranking summary to focus only on 4 chronic cardiovascular diseases yields a similar pattern:

FT3 is still the most intense row. Now the step from Low FT3 to Normal Q1 is 3x the distance in the ranking of prevalence rates. High-normal TSH is still the next hot spot.

Now the red color is more evenly distributed. Notice that the 3 types of hypothyroidism (low FT4, high TSH, low FT3) are color coded red.

Why do doctors associate hyper with cardiovascular symptoms and tend to ignore the association with hypo?

Four conclusions

These 10 chronic diseases cost our health care systems a lot of money and can cause great human suffering over a lifetime.

We can’t afford to separate thyroid hormone levels from chronic disease when they give us such major clues about how to manage these diseases more wisely.

Here are some suggested action items:

  1. Distinguish acute from chronic Low T3 syndrome (NTIS)
  2. Treat and prevent low T3 syndrome.
  3. Stop excluding thyroid patients from NTIS study and treatment.
  4. Call for a T3 paradigm shift in thyroid science

1. Distinguish acute from chronic Low T3 syndrome (NTIS)

The data say nothing about the duration of low T3 syndrome, but 15% of the FT3-tested population fit in that category.

The acute (and often benign) phase of NTIS must be distinguished from the pathological state of chronic low T3 that demonstrates a critical failure to recover a vital hormone supply (Moura Neto & Zantut-Wittmann, 2016; Van den Berghe, 2014).

Chronic low Free or Total T3 and chronic low T3:T4 ratios are not just effects of illness, but can also become pathological drivers and maintainers of illness.

Many decades of research in NTIS have shown that a weak TSH response and/or thyroid gland response can perpetuate a low Total or Free T3 level and T3:T4 ratio, leading to increased rates of poor health outcomes and death. (NOTE: In severe illness, the Total T3 is often used instead of Free T3 because some illnesses and blood thinners like heparin can artificially inflate Free hormone test results.)

Look at the T3:FT4 ratios of people with heart failure:

“Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF.”

Kang et al, 2017

The chronic low T3 levels and T3:T4 ratios during chronic disease are prognostic of future problems.

This is the case in many types of chronic illness including renal failure, cardiovascular diseases, not just in acute conditions demanding intensive care (Ataoglu et al, 2018). (See our review of Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.)

2. Treat and prevent chronic low T3 syndrome.

Enough research has catalogued the high rates of death and morbidity in Low T3 Syndrome (also called mistakenly called “euthyroid sick syndrome” just because TSH usually remains normal).

Yet publications continue to repeat the skeptical medical stasis that

no clear consensus has emanated from clinical studies”

of thyroid hormone interventions, so

“many scholars suggest that treatment of the primary disease takes precedence over ESS [euthyroid sick syndrome] intervention.”

Wang et al, 2018

However, quotes like these reveal an arbitrary, false division between the “primary disease” (such as heart failure) and a thyroid hormone metabolism disorder such as ESS, when thyroid hormone signaling clearly modifies primary disease outcomes.

Thyroid scientists with courage have previously advocated for more NTIS treatment trials involving T3 (DeGroot, 2006), but it seems to have fallen on deaf ears. The considerations of treatment are complex, but few have the courage to face them for the sake of saving lives, health care dollars, and human suffering.

If we supply ventilators and oxygen to people who cannot breathe, then it is unethical not to assist the thyroid-healthy human body to recover healthy FT3 levels and FT3:FT4 ratios to prevent the progression of a chronic disease.

Patients with chronic diseases deserve to access FT3 thyroid hormone levels and ratios that are conducive to their recovery.

3. Stop excluding thyroid patients from NTIS study and treatment

This research by Anderson and team unfortunately excluded from their main data set all people dosed with thyroid hormone because of our complexity.

There were 37,288 people excluded from Anderson’s study for this reason. No data tables were provided for them, no explanation of their quartile divisions, and no FT3 or TSH prevalence data was provided. We were only given a verbal summary of the FT4 odds ratios that the researchers felt were most important as they looked for linear trends within the reference range.

This is a significant loss of data. We have insufficient knowledge of a neglected population.

It is very disturbing that thyroid patients are routinely excluded from low T3 syndrome / nonthyroidal illness (NTIS) research, as we’ve discused in previous posts.

As a result, only a handful of small-scale studies have examined NTIS in treated patients, one of them a biased study of 6 men on Synthroid who underwent NTIS after surgeries. This study only proved that treated patients are not immune to the biochemical phenomenon of Low T3 Syndrome.

It cannot reassure any reasonable reader that patients on LT4 monotherapy will, on average, recover at the same rate as untreated people with healthy thyroids.

Consider the cruelty and irresponsibility of this research exclusion. Treated thyroid patients are a more medically vulnerable cohort than the health-thyroid population. Their hormones and TSH are medically manipulated, not naturally acquired and metabolized partly by a healthy thyroid gland, now removed, that once expressed most of the Dio1 and Dio2 enzymes in their body. Even at a normalized TSH, their Free T4 and Free T3 are not likely to be adjusted in the way a normal healthy TSH-thyroid partnership would configure them.

Presuming that a treated, thyroid-disabled person’s TSH-FT4-FT3 configuration is risk-free is like presuming that a woman without a man’s traditional symptoms of heart attack is not at risk of having a heart attack.

Unfortunately, medical schools do not routinely teach the narrow index of individuality (IOI) in thyroid hormone reference ranges that exists even in untreated people. As a result, many patients are forced to suffer for decades with thyroid hormone levels and ratios ill-suited to their individual metabolic needs while a therapy lacking any T3 manipulates their TSH to suit current medical opinion. An unintended pharmaceutical T3-ectomy may be the price of obtaining the target TSH concentrations that a doctor naively believes signifies euthyroidism for every human being.

  • Will their chronic low-normal Free T3, high-normal Free T4 and high-normal TSH take advantage of a familial susceptibility for renal failure, hastening its progression to stage 4 despite treatment?
  • How will their renal failure further lower their FT3 and plunge them into nonthyroidal illness (NTIS)?
  • How can they ever recover enough FT3 to support kidney and cardiac function if they lack a TSH-thyroid partnership capable of restoring their thyroid metabolic health?

Therefore, treated thyroid patients deserve an even deeper analysis of their progression through NTIS, including their LT4 and LT3 or desiccated thyroid therapy dosages, antibody status, and thyroid disease etiologies.

One can only hope that in a future publication, Anderson’s data tables of prevalence rates will be provided for this treated subset for all 10 diseases examined for the untreated population.

We need to know this population’s unique quartile divisions and their FT3:FT4 ratio data, not just see this population always presented through the lens of healthy-thyroid population statistical norms.

Consider that it is inappropriate to continually view a unique population through the lens of another population’s statistics. It’s like presenting women’s sex hormone data through the lens of men’s sex hormone statistical parameters, or presenting pregnant women’s thyroid hormone data always through the lens of non-pregnant women’s thyroid hormone statistical parameters.

And may long term LT3- and NDT/DTE-dosed populations also be included in future studies, to enable comparison of their disease prevalence rates with those on T4 monotherapy.

4. Call for a T3 paradigm shift in thyroid science

In 2014, the American Thyroid Association published a set of “Guidelines for the treatment of hypothyroidism” (Jonklaas et al, 2014).

This is what they had to say about T3 concentrations:

The ATA guideline quotation above is the opening of a section that attempts to minimize FT3 hormone testing recent studies of thyroid therapy. By calling T3 levels “mildly low,” “perturbations” and “variations,” it represents the only T3 fluctuations that are likely to occur as minimal in degree, and therefore implicitly minimal in clinical significance.

If you search the Jonklaas 2014 ATA guidelines for the word “unknown,” you will find it occurs 8 times in the document, and always in reference to T3 and to the enzymes that convert T4 to T3. No other aspect of hypothyroid therapy, apparently, is remarkable enough to warrant an emphatic declaration about its being unknown.

What a shameful admission of ignorance of our most potent thyroid hormone — and without any literature review of research on T3 hormone in chronic diseases during nonthyroidal illness syndrome.

It makes it appear that a repeated claim of research-based ignorance, poorly proven with a thorough search, is being used as justification to hold to a now traditional policy, since the 1990s, guarding against FT3 testing and optimization of FT3 levels in favor of testing only TSH and occasionally FT4.

How could they be so bold in claiming that there was nothing known?

Click to read more in-depth analysis

First of all, it’s because this document is about treatment of hypothyroidism, even though this passage seems to be about everyone’s T3. They claim that the health significance of “mildly low” T3 concentrations is unknown, because UNtreated people’s low T3 health outcomes are unknown. As mentioned above, there is a long, shameless tradition of excluding treated thyroid patients from the study of Low T3 Syndrome / Nonthyroidal illness.

I have not yet been able to discover treated thyroid patients’ disease prevalence or risk of renal failure or atrial fibrillation at various FT3 hormone levels within and beyond reference range. Can you?

How can treatment guidelines build policies on ignorance about such fundamental matters?

Secondly, it is because within thyroid therapy research, there is a strong tradition of associating only thyroid patients’ TSH levels (and sometimes FT4 levels) with health and disease while minimizing or ignoring precise FT3 levels and FT3:FT4 ratios within and beyond reference range in relation to health and disease.

An illustrative example of TSH-T4 paradigm T3-blind research

For example, in a research study on dementia in hyperthyroidism (Folkestad et al, 2020), this was the conclusion, devoid of any insight into associations between FT3 and FT4 levels and dementia:

“For every 6 months of decreased TSH there is a 16% relative increased risk of dementia compared to individuals with normal TSH.”

Their methods were T3-blind. They presumed TSH would have the strongest association with dementia, and they unsurprisingly discovered only what their narrow methods allowed them to see.

After Total T3, Total T4 and TSH were used to classify people into Euthyroid, Overt Hyper and Overt Subclinical diagnostic categories, Folkestad and team did no collection of FT3 or FT4 data or FT3:FT4 ratios for the sake of associating thyroid hormone levels with dementia. Is anyone thinking of these questions when reading their study:

  • What is the risk of dementia every 6 months that FT3 are elevated above reference range?
  • Was the duration of FT3 above range less than the risk of duration for FT4 above range or TSH below range?
  • Did the FT3:FT4 ratio matter when both hormones were above range, or was FT3-dominant hyperthyroidism less associated with dementia?
  • Why must health outcomes be associated with being “in or out” of range, instead of health outcomes telling us where the physiological boundary is found in certain classes of disease and treatment?
  • How about the normal quartiles of FT3 in subclinical hyper? What if they had stronger associations with dementia than their Subclinical/Overt diagnostic criteria?

Apparently these questions are not worthy of being asked, otherwise the journal reviewers would have asked them to address them.

Apparently it’s okay to ignore FT3 and health, but one must never, ever, omit examining the relationship between TSH and health?

It is presumed that the human body respects our population statistical reference range boundaries and diagnostic categories, the low TSH boundary being the most significant of all. Instead of asking “how high can the FT3 or the FT3:FT4 ratio rise before it significantly increases risk of dementia?”, now the only question left is one of degree, “just how significant is normal vs. low TSH?” — in comparison with nothing else.

The injustice of silencing FT3 and disconnecting it from health outcomes

Here’s an analogy. In cultures that do not permit women to hold authority in homes or workplaces, it is very easy to also forbid them from voting. The simple hierarchy is Men > Women. Similarly, endocrinology research has instituted a hormone hierarchy TSH > FT4 > FT3 that people feel a need to reinforce and validate in research as well as practice. The procedures and presumptions in research are serving and reinforcing the current policies for testing and treatment.

When it comes to their influence on human health, thyroid hormones are not being permitted to speak for themselves. In the TSH-T4 paradigm, thyroid hormones must always be “spoken for” by the voice of TSH secretions, statistical reference ranges boundaries, and diagnostic categories. TSH is treated like the FT3:FT4 proxy, but it is not a proxy of T3 signaling in all extrapituitary tissues. No matter how sensitive its unique pituitary TR-beta2 receptors are to their own local rate of thyroid hormone conversion, TSH secretion is a tissue-specific biomarker.

Another hallmark of this paradigm is a focus on TSH concentrations rather than understanding TSH receptor signaling. In Folkestad and team’s research on dementia, despite the strong emphasis on low TSH and the calculation of a numeric relative risk, there was no measurement of Graves’ disease antibody titres. It would only be rational to determine whether TSH receptors were being hyperstimulated by antibodies in the pituitary gland and artificially lowering the TSH through the ultrashort feedback loop, since this has been known since 2003 and 2004. Instead, researchers appeared to hold the naive belief that low TSH concentrations purely and directly represent thyroid hormone feedback without any antibody interference in Graves’ disease patients. We must assess TSH-receptor signaling, not merely assess TSH, because TSH is not the only “ligand” that signals in its receptor.

We need a paradigm shift.

The TSH-T4 paradigm has biased and blinded decades of thyroid research with unphysiological hormone hierarchies, omissions, and presumptions.

It has prevented our healthcare systems from seeing FT3 and the FT3:FT4 ratio’s far greater power over human health than mere TSH concentrations in or out of range.

It deceives some doctors and scientists into believing there is nothing known, and nothing worth knowing, about the way FT3, in relationship to FT4, can play a disease-modifying role in chronic cardiovascular, neurological, and metabolic disorders.

You’ve seen how strongly FT3 concentrations in and beyond range can associate with disease prevalence. You see that FT3:FT4 ratios can make some distinctions clearer.

The TSH-T4 paradigm has not only promoted the exclusion of thyroid hormone-treated people from the study of the health outcomes of Low(er) FT3 hormone levels.

It has also promoted the exclusion of the FT3 hormone concentration from the study of thyroid hormone-treated people’s health outcomes.

It’s up to us to make a change. Refuse to accept the continued exclusion that separates the most vulnerable thyroid-disabled people from the most powerful thyroid hormone concentration, Free T3.

It’s time to renew the paradigm of thyroid therapy.

  • Tania S. Smith

How to read the “category diagnoses” in the tables

Click to expand’s additional computations were based on Anderson’s data plus other scientific research:

  1. FT4, TSH and FT3 data for each hormone level were translated to “percent of reference range.” This enabled comparison between three hormones that had three different reference ranges and units of measurement. American units such as ng/dL are not standard international units.
  2. Traditional diagnostic criteria were applied to hypothyroid, hyperthyroid, and non-thyroidal illness (NTIS), according to highly respected recent scientific publications (see details below).
  3. The ratio of average FT3 to FT4 in pmol/L was calculated for each cohort. It is a “ratio of averages,” rather than a true “average ratio.” (Other researchers calculate each person’s FT3:FT4 ratio and then average the ratios. This can lead to a slightly different result. See Strich et al, 2016 and Gullo et al, 2011).
[TH = Thyroid hormones FT3 and FT4. The analysis methods are explained in more detail below.]

Three types of Hypothyroidism

Three subtypes of hypothyroidism (including tissue hypothyroidism, NTIS) were found in three of Anderson et al’s hormone levels:

  1. Isolated Low FT4 level: Overt hypothyroidism, with a high FT3:FT4 ratio and high TSH.
  2. Highest TSH level: Overt hypothyroidism, but with a much lower FT3 and the highest average TSH.
  3. Isolated Low FT3 level: “Nonthyroidial illness syndrome,” (NTIS), or “Low T3 syndrome.
Click to read the details on each
  1. Isolated Low FT4 level: Overt hypothyroidism, with a high FT3:FT4 ratio and high TSH.
    • Overt hypothyroidism is defined by Garber et al, 2012 ATA/AACE guidelines.
    • This pattern of laboratory results is commonly seen in early mild Hashimoto’s Thyroiditis at diagnosis, as the FT4 normally falls below range long before FT3 does, due to TSH upregulation of D1 and D2 enzyme in the thyroid gland and peripheral tissues.
    • A higher TSH also stimulates a higher FT3:FT4 ratio of thyroidal secretion if a significant thyroid gland fragment remains (Hoermann et al, 2020).
  2. Highest TSH level: Overt hypothyroidism, but with a much lower FT3 and the highest average TSH.
    • In this study, the highest TSH level among 147,834 adults was 501.92 mcIU/L. This group likely had its average TSH skewed high by some extreme cases of untreated autoimmune hypothyroidism involving TSH receptor-blocking antibodies (TBAb).
    • TBAb antibodies can induce an extremely high TSH and low FT3:FT4 ratio by blocking TSH-receptor signaling in the thyroid and throughout the body, affecting T4-T3 conversion even within the pituitary gland. It is a lesser known and very different form of hypothyroidism than that caused only by the well-known Hashimoto’s anti-TPO (thyroid peroxidase) antibody. Learn more about the overlooked entity of autoimmune “blocking-type hypothyroidism” (called this by Tagami et al, 2019), including Atrophic Thyroiditis, caused by TBAb antibodies. Several antibodies overlap and can coexist in the full spectrum of thyroid autoimmunity, so some of these patients may have Hashimoto’s in addition to TBAb autoimmunity.
  3. Isolated Low FT3 level: “Nonthyroidal illness syndrome,” (NTIS), or “Low T3 syndrome.
    • This category is defined by Van den Berghe’s 2014 review on “Non-Thyroidal Illness in the ICU.”
    • In the past, it has been controversial to classify NTIS as a form of “hypothyroidism,” yet Mancini et al, 2016 argue that “The presence of OS indexes in NTIS supports the hypothesis that it represents a condition of hypothyroidism at the tissue level and not only an adaptive mechanism to diseases.” The TSH does not need to be elevated for a state of “hypothyroidism” to exist, as TSH can be low or normal central hypothyroidism (Persani et al, 2019).
    • NTIS always presents with low FT3. This category also had the lowest FT3:FT4 ratio, the inverse of the type of hypothyroidism seen in early-stage Hashimoto’s thyroiditis, showing that it is a dysregulated thyroid metabolism (Moura Neto & Zantut-Wittmann, 2016).
    • Here, the cohort on average also had a high-normal TSH at 59%, not an elevated TSH. During natural recovery from NTIS, TSH rises within and even above range as the body attempts to recover from low FT3 (Moura Neto, 2016; Van den Berghe, 2014). However, the FT3 will remain low if natural recovery fails (if TSH does not rise enough to stimulate, or TSH cannot coax a thyroid gland to secrete enough to raise the FT3).

Three types of Hyperthyroidism

Three subtypes of hyperthyroidism were found within the opposite hormone level categories. The subtypes were associated with different FT3:FT4 ratios and levels:

  1. High FT4 level: Overt hyperthyroidism, with a moderate FT3:FT4 ratio
  2. Low TSH level: Subclinical hyperthyroidism, with high-normal thyroid hormones
  3. High FT3 level: Overt hyperthyroidism, with a high FT3:FT4 ratio.

Click to read the details on each

The two categories of High FT4 and High FT3 were defined as “overt hyperthyroidism” mainly on the basis of their extremely high FT3 and FT4 averages (From 124% of range FT4 to 257% of range FT3), not on the basis of their TSH.

  • These categories also had an average TSH of -2% of range and 0% of range. Therefore, not everyone could have had a low TSH.
  • These categories could have included some persons with a borderline low or low-normal TSH despite a mildly elevated FT3 and/or FT4.

Some autoimmune Graves’ disease patients are very “FT3-dominant” due to their TSH-receptor antibody expression.

The Graves’ antibody’s effect works through the TSH receptor. The TSH receptor (TSHR) stimulating signaling overstimulates the thyroid gland even in the absence of TSH in blood.

This TSHR signaling complexity in autoimmune hyperthyroidism may explain the differences between the two categories’ FT3:FT4 ratios.

  • The stimulating antibody (TSAb) is like a super-powered TSH that enhances the TSHR signal. You can think of the stimulating antibody as “invisible TSH.”
  • In contrast, the Graves’ blocking antibody (TBAb) inverts the TSHR signal to below the baseline signal produced by an empty TSH receptor; the blocking antibody is an “inverse agonist.” (McLachlan & Rapoport, 2013).
  • Some hyperthyroid patients a TSAb-dominant antibody phenotype, whereas others have concurrent TBAb and TSAb antibody expression or flip back and forth between these two antibodies over time (Wong & Inder, 2018).
  • If TBAb are present at the same time as TSAb, the blocking antibody can dampen the escalation of FT3.

Therefore, it is not the absence of TSH that harms people with Graves’ hyperthyroidism, but rather the way the TSAb stimulating antibodies take over the TSH receptor to overstimulate the thyroid gland to hypersecrete and the entire body to hyperconvert T4 to T3.

In Graves’ hyperthyroidism, the D1 enzyme that converts T4 to T3 tends to be upregulated (Chen et al, 2018). That means that D1 is overactive in three glands where DIO1 gene is most strongly expressed: Thyroid gland, liver, and kidney.

Subclinical hyperthyroidism, cases of low or suppressed TSH with normal thyroid hormones, has long been a respected diagnostic category.

  • In untreated populations, subclinical hyper can occur not only in mild Graves’ disease but also in people with autonomous functioning thyroid nodules.
  • However, a minority of patients in this category may have central hypothyroidism, with TSH is low while FT3 and FT4 are in low-normal part of reference. “Hidden or mild forms of CeH [central hypo] are usually characterized by FT4 in the lower part of the normal range” (Persani et al, 2019). In central hypo, the pituitary secretion of TSH is incapable of rising appropriately to signal the fall of FT3 and FT4 to almost subnormal levels.  

Why is the ratio of average FT3:FT4 important?

The ratio of FT3 to FT4 appears to be a basic principle in normal thyroid hormone economy when no thyroid hormone dosing and no thyroid disease interferes.

This ratio is an indicator of the normal or abnormal response of the individual’s thyroid gland and thyroid hormone metabolism to the level of TSH-receptor stimulation.

The ratio of FT3:FT4 can be judged low, normal, or high when expressed in pmol/L and compared with Gullo et al, 2011’s healthy control group of 3,875 people, and Strich et al, 2016’s study of 27,940 untreated patients at all ages.

  1. Gullo and team discovered that the average ratio among healthy controls is approximately 0.32-0.33 and the reference range was from 0.20 to 0.50.
    • Anderson’s data set coincidentally fits almost perfectly with Gullo’s range and average. Mid-range ratios of average FT3:FT4 in the table are approximately 0.33 pmol/L. The lowest ratio was 0.24 and highest ratio was 0.53.
  2. Gullo found that this average ratio was constant across all normal levels of TSH in the healthy population.
    • Anderson’s TSH normal quartiles coincidentally agree with Gullo’s finding; they express 0.33-0.34 ratio across the entire normal range.
  3. Strich found that the FT3:FT4 ratio decreased decade by decade from childhood to advanced age, but did not change much between age 30 and 60.
    • Anderson’s ratio average within TSH Normal Q1-Q4 is 0.3325 and the average age of the population was 64.9 years.
    • Strich et al’s ratio average within TSH Normal Q1-Q4 is 0.345 in the 60-70-year-olds category.
For advanced scientific readers: Learn how this ratio is adjusted in the human body

As TSH rises, the ratio normally rises (T3 rises more than T4 does) in a state of gland health and metabolic health. Two things happen in the thyroid:

  1. TSH-receptor stimulation preferentially stimulates T3 synthesis in the thyroid gland, adjusting the ratio of thyroidal secretion (Citterio et al, 2017; see “T3 is not always converted from T4: De novo T3 synthesis“.)
  2. TSH-receptor stimulation in the thyroid gland also stimulates D1 and D2 enzymes that convert T4 to T3 as blood flows through thyroid tissue.

When these 2 things (synthesis + internal thyroid hormone conversion) are added together, you get the “secretion ratio” of the thyroid gland increasing the T3:T4 ratio produced per unit of TSH, enhancing FT3 in blood. (Laurberg, 1984)

This T3 boosting function of TSH in the thyroid gland is called the “TSH-T3 shunt” (Berberich et al, 2018).

TSH-receptor signaling also enhances the D1 and D2 enzymes throughout the rest of the body, since these enzymes are expressed in every organ and tissue.

In cases of autoimmune hyperthyroidism, sometimes non-TSH stimulators are involved in escalating the FT3:FT4 ratio, such as TSH-receptor stimulating antibodies (TSAb) in Graves’ hyperthyroidism. By the same mechanism, the TSH-receptor blocking antibodies (TBAb) in autoimmune hypothyroidism can reduce the FT3:FT4 ratio by blocking TSH receptor signaling.

Only Free T3 and Free T4 can be transported into cells where conversion occurs via D1, D2, and D3 throughout the body. Each tissue in the body converts T4 and T3 at different rates to adapt bloodstream hormone levels to that tissue’s current metabolic needs. Some tissues are more efficient at converting T4 than others.

Converted hormones are transported out of cells at the same rate that hormones enter the cell, to keep equilibrium within the cell. The 2-way exchange of hormone between bloodstream and cells happens every minute of every day, but some tissues may exchange hormone at a slower rate (bones, for example).

The bloodstream FT3:FT4 ratio, therefore, reflects both T4 and T3 supply and the net product of T4-T3 conversion in cells throughout the body. This is why the ratio can be used to calculate “Global Deiodinase efficiency” (GD) (Midgley et al, 2015)

Click to read about differences in thyroid-disabled, treated patients

Outside of thyroid therapy, abnormal ratios and levels are a clear signal of either thyroid gland dysfunction, pituitary gland dysfunction, or thyroid metabolic dysfunction, because the TSH-stimulated thyroid and feedback loop have physiological parameters that are uninfluenced by dosing.

However, in thyroid therapy, normal biochemistry is not a fair standard of judgment of patients’ health risks. True physiological mimicry is impossible for many people after thyroid loss. When you add thyroid tissue loss to a hormone treatment absorbed in pulses through the GI tract, it can skew all these hormones artificially.

Sometimes treated thyroid patients can only find euthyroid metabolic status with unusual TSH, FT4 and FT3 levels and FT3:FT4 ratios that compensate for their disability.

Four differences

1. The TSH feedforward loop works differently in untreated people.

  • In persons with healthy thyroid glands, TSH in Anderson’s high-normal Q4 can stimulate the thyroid to secrete higher levels of FT4 and FT3. It also results in higher FT3:FT4 ratios, as seen in cases of metabolic syndrome (Kim et al, 2016).
  • In contrast, during thyroid loss and thyroid therapy, TSH is skewed lower per unit of FT3, and therefore, a high-normal TSH can indicate genuine tissue hypothyroidism in some patients (Larisch et al, 2018; Hoermann et al, 2013).

Scientists who studied and compared many biomarkers under T4 dosing and T3 dosing have found that in T3-dominant therapies, a normalized TSH during therapy “does not necessarily equate to a state of generalized euthyroidism at the level of the different targets of hormonal action” (Yavuz et al, 2013).

There is a biological explanation for this. The pituitary and hypothalamus organs must presume that a thyroid gland is the primary source of the highest hormone level it senses. These glands are not designed to adapt perfectly to ratios induced by thyroid hormone pharmaceuticals absorbed in pulses through the GI tract. The pituitary TSH feedback loop is poorly equipped to judge the overall metabolic status of the significantly lower or higher FT3:FT4 ratios than a thyroid can produce.

For example, when a very low FT3:FT4 ratio is present, such as the low ratio induced by T4 monotherapy in a “poor converter” (Midgley et al, 2015), TSH adjusts to the isolated high FT4 alone while being blind to the deficiency of the lower FT3.

  • Even in undosed people, it is well known that TSH cannot rise to signify genuine hypothyroidism in tissues when only the FT3 is low but FT4 is in normal range, and you can see this in the “NTIS / Low T3 syndrome” cell of the table.

The opposite happens in FT3-dominant therapies, with TSH suppressing too far based only on the temporary peak FT3 level a few hours post-dose.

  • Even in undosed people, TSH can over-suppress when only the FT3 level is dominant while both hormones are in normal range. This is because TSH must lower to forestall a healthy thyroid gland’s overstimulation. You can see this happening in the “Low TSH / Subclinical hyper” cell of Anderson’s data.

2. Thyroid gland metabolic disability varies from person to person.

Thyroid patients have an injury, disease or loss that has compromised the human body’s most powerful metabolic engine for T4-T3 conversion.

The thyroid gland is not just a secretor of hormone. The thyroid expresses the vast majority of the human body’s DIO1 and DIO2 mRNA.

Because of the TSH-T3 shunt (described above), the healthy, flexible TSH drives up T4-T3 conversion in the thyroid more than anywhere else in the body. After thyroid loss, the human body becomes far more vulnerable to DIO1 and DIO2 polymorphisms because there is less potential D1 and D2 expressed in the body.

Scientists already know this fundamental shift in supply and metabolic deficiency results in altered TSH-T3 relationships in the T4-treated population, significantly lower FT3:FT4 ratios, and an inability to mimic normal FT3 circadian rhythms of night-time FT3 elevation.

3. The FT3:FT4 ratio is skewed by dosing in ways that require compensation and adaptation.

Thyroid removal replaced by T4 monotherapy, for example, significantly reduces the FT3:FT4 ratio (Gullo et al, 2011). T4 monotherapy is an inherently unnatural dosing ratio because the thyroid always secretes T3 along with T4.

Conversely, Graves’ disease antibodies raise this ratio significantly by elevating D1 enzyme expression (Chen et al, 2018).

The lower ratio in T4 monotherapy is a metabolic handicap that makes a higher FT4 necessary to raise FT3 to average population levels mid-range or higher. Each unique thyroid-disabled patient experiences relief from tissue hypothyroidism at a slightly different FT3 level, and often a lower-than-normal TSH is necessary to maintain a metabolically euthyroid state (See Hoermann et al, 2019 and Ito et al, 2017, 2019).

However, some patients are poor converters of T4 hormone (Midgley et al, 2015) who may not be able to achieve their individually optimal FT3 levels without the aid of T3 dosing.

Optimal FT3 and FT4 levels are highly individualized, even in a state of perfect thyroid and pituitary health, where the TSH adjusts the FT3 and FT4 level very precisely to a narrow part of reference range–some people are high in range, some are lower. The “index of individuality” is so narrow and unique in thyroid hormones that merely targeting the population “average” or staying in the wide population statistical “range” for TSH, FT3 or FT4 is never precise enough to induce euthyroid status in all individuals.

In thyroid therapy, individual adjustment must be done manually with full participation of the patient.

4. When a high FT3:FT4 ratio is induced intentionally by T3 dosing, it can be therapeutic and euthyroid.

First, consider what nature does to compensate for the two most common causes of hypothyroidism. Nature raises the FT3:FT4 ratio to maintain euthyroidism in both 1) early autoimmune thyroid failure and 2) iodine deficiency.

  1. In early thyroid failure, the FT3:FT4 ratio is very high, as you can see in Anderson’s “Low FT4” category. The TSH rises high to push FT3 up.
  2. Likewise, when FT4 falls low in iodine deficiency, FT3 can rise above reference when necessary to maintain euthyroidism. The TSH rises high to push FT3 up.

This is nature’s compensation for a lower FT4 — T3 is “dosed” from the thyroid gland by raising the TSH-receptor stimulation of the thyroid.

When humans dose T3 pharmaceutically, we do not need to use TSH to accomplish this task. Instead, the post-T3-dose peak that occurs in FT3 artificially lowers the TSH. However, the dosing of T3 hormone can have the same enhanced FT3:FT4 ratio effect as if the TSH was normal to high and inducing the altered FT3:FT4 ratio.

Abnormally high FT3:FT4 ratios in thyroid therapy are not harmful when they are properly adjusted to induce euthyroidism.

These ratios do not require “normal TSH” to signal that euthyroidism exists, because normal TSH is not needed to create or maintain these ratios when dosing.

Balance is the principle.

  • Avoiding thyrotoxicosis: A fluctuating and mildly elevated FT3 part of the day won’t become thyrotoxic if it is counterbalanced with an appropriately moderate to low level of FT4 for the individual, and,
  • Avoiding hypothyroidism: When the FT3 is high enough for an individual, it prevents hypothyroidism from resulting from a lower FT4.

Euthyroid metabolic status can even be achieved in 100% T3 monotherapy in exceptional persons whose bodies cannot tolerate LT4 dosing for various reasons (Khan & Wheatley, 2016; Kawakami et al, 2007; Hlaihel and Al-Khairalla, 2019).

How to read the patterns in reference range

In the graphic above, each hormone’s set of 4 quartiles changes one hormone variable while holding another variable almost constant.

This makes each hormone category unique. It enriches the data set with diverse hormone profiles for comparison.

Such differences may give clues to help us understand, for example, why the disease prevalence rate for TSH in Q1 is different from FT4 in Q4.

Click to read details on the differences among “normal” quartiles

Top row, Normal FT4 quartiles:

  1. FT4 in Q1: Lowest FT4 with the highest FT3:FT4 ratio within reference
  2. FT4 in Q4: Highest FT4 with the lowest FT3:FT4 ratio within reference

FT3 remained fairly constant in this row, only increasing slightly from 23% to 31% of range from Q1 to Q4 (only 8% variation).

TSH varied widely and inversely with the FT4, decreasing from 45% to 17% from Q1 to Q4 (28% variation).

Middle row, Normal TSH quartiles:

  1. TSH in Q1: Lowest TSH in reference, ratio normal
  2. TSH in Q4: Highest TSH in reference, ratio normal

In this row, the average TSH ranged widely, from 7% to 74% of reference (67% variation). However:

  • FT4 varied little across the row, only decreasing from 37% to 27% from Q1 to Q4 (10% variation), hardly changing at all from Q2 to Q3.
  • Likewise, the FT3 varied even less across the row, from 23% to 17% from Q1 to Q4 (only 6% variation), hardly changing at all between Q1 and Q3.
  • Thirdly, the ratio of average FT3:FT4 held almost constant across the row, from 0.33 to 0.34.

Bottom row, Normal FT3 quartiles:

  1. FT3 in Q1: Lowest FT3 in reference with a low FT3:FT4 ratio
  2. FT3 in Q4: Highest FT3 in reference with a high FT3:FT4 ratio


  • The FT4 variable was held almost constant, only rising slightly from 33% to 40% from Q1 to Q4 (only 7% variation).
  • The TSH varied less than half as much as it did among FT4 quartiles. TSH only decreased from 27% in Q1 to 16% in Q4 (a change of -11% in the FT3 row, compared to 28% in the FT4 data row).
  • The ratio of average FT3:FT4 also varied a little less widely compared to the FT4 data row, rising from 0.30 to 0.39 from Q1 to Q4 (only a 9% variation, vs. 12%).

Anderson’s Free T3 distribution is abnormally low: Was there a testing bias?

For advanced scientific readers: Click to expand

How many people were low, normal, or high?

An unequal percentage of patients were distributed among low, normal, and high levels:

Free T4 TSHFree T3
Low7.4% 22.8%15.0%
Normal Q1, Q2, Q3, Q488.4%70.0%79.9%
Percentage of patients with low, normal, and high levels.

What kinds of FT3 test-ordering biases exist?

Currently, in thyroid laboratory testing flowcharts being promoted by organizations like Choosing Wisely Canada (and international branches of the organization), FT3 is recommended as a test ONLY when TSH is low and FT4 is normal.

This is only to check whether TSH is being suppressed by an elevated FT3. (If TSH is not suppressed by elevated FT3 or FT4, it may be suppressed independently by Graves’ TRAb antibodies, so a TRAb test is in order.)

This test-ordering bias presumes that FT3 testing has only one purpose: To screen for untreated or poorly treated hyper-thyroidism.

This is a testing bias that is blind to chronically poor T4-T3 conversion, a disorder of thyroid hormone metabolism. Unfortunately, low T3 syndrome is often considered not worthy of testing for because it has been incorrectly presumed to be benign, temporary, and untreatable (Van den Berghe, 2014).

If the TSH and FT4 lab test preconditions are not met, the FT3 will sometimes be cancelled by the lab using the flowchart, even if FT3 was ordered by the doctor. Sometimes doctors will be “reeducated” not to order FT3 in the first place, once they are indoctrinated into standard beliefs about FT3:FT4 ratios and health risk.

Obviously this test-cancellation policy has no ethical concern about whether FT3 or the FT3:FT4 ratio is too low for health.

However, Anderson’s data set begins in 1999, likely before these test-ordering biases were built into policy.

In Anderson et al’s study, there was no evidence of flowchart-based FT3 test-ordering bias within the data set.

The team looked for such test-ordering biases and addressed them in a section of their study that ruled them out.

The average TSH and FT4 levels among those who were also tested for FT3 showed no expected bias toward low TSH data or high FT3 data. In the TSH data set, 7.2% had a low TSH. Yet only 5% of the people whose FT3 was tested had a high FT3, while 80% had a normal FT3, and 15% had a low FT3.

Low T3 is not detectable by following our biased contemporary TSH and FT4 testing flowcharts. Isolated Low T3 is the main feature of “nonthyroidal illness syndrome” (NTIS). TSH only falls low 10% of the time in nonthyroidal illness (Ganesan et al, 2020). More commonly, acute and chronic NTIS limits TSH from rising in response to Low FT3, but TSH is usually normal until it rises during the recovery phase (Van den Beld, 2015).

Was there bias in testing FT3 in more severe disease?

Anderson and team claimed there was no evidence of bias.

First of all, this study could not screen out unhealthy people and people with extreme hormone levels. That would have defeated their purpose. The main point was to associate hormone levels with illnesses like Atrial Fibrillation.

Regardless, the people tested for FT3 were not “more severely ill” than people tested for TSH or FT4 because:

  • The prevalence rate of atrial fibrillation in the FT3-tested population was 4.1% on average. This was slightly lower than among people whose FT4 alone was tested (4.5%), and people whose TSH was tested (4.5%).
  • As shown below, the vast majority of people tested for FT4, TSH and FT3 had lower than average disease prevalence rates, not higher, in the FT3 quartiles in the normal range or higher (FT3 in normal range or higher is usually colored green/teal for lower disease prevalence).

And finally, there is evidence that many of the FT3 tests were ordered as a set of three tests (TSH, FT4 and FT3), without a separate decision made about whether or not to order FT3.

  • There was an average of only 1.46 days between the Free T4 and Free T3 test.

Then why was the FT3 data skewed lower than it is in healthy people?

Anderson’s median FT3, at 22% of reference, was biased lower than it is in the healthy population (around 50% of reference).

In well-screened healthy, untreated populations, the FT3 average is at mid-range (Ganslmeier et al, 2014). The bell curve is very tall and narrow because the majority of the healthy population has FT3 values at mid-range.

Again, it’s because these were not healthy people. So that’s just the way the data set is — and it’s why their “FT3 Normal Q4” encompasses more than the upper 50% of reference of range.

(NOTE: The FT3 is often significantly lower than the population average in people treated with standard LT4 monotherapy, but this data set excluded people on thyroid hormone treatment.)

The low-skewed FT3 is also due to sex and age.

Anderson’s entire cohort was biased toward women (64.9% women). In addition, there was a bias in ordering FT3 more frequently in women (71-79%) than in men (21-29%).

  • Autoimmune hyperthyroidism and hypothyroidism are both found more commonly among women. In this cohort, 30% of the population had abnormal TSH results.

Anderson’s entire cohort’s age (64.9 years) was the second variable for making FT3 on average skewed not higher, but lower, as the data show.

  • Children aged 1-10 have the highest average FT3 levels. Until age 30, FT3 level on average is still significantly higher than the mean. The FT3 mean gradually falls in age groups between 30-60 years of age. Then FT3 drops lower after age 60, and often plummets after age 80 (Strich et al, 2016).
  • This finding was reflected in Anderson’s data as the average age dropped as FT3 level rose higher.
    • Anderson’s youngest population was found in the High FT3 group (mean age 58.7, which 6.2 years younger than the study population mean of 64.9).
    • In contrast, Anderson’s oldest population was found in the Low T3 group (mean age 65.5, but only 1 year older than the entire cohort).

Details on calculations

Click to read further details

Why convert to percent of reference? In a table of data, translating all hormone values to percent of reference range enables easier diagnosis of how high or low each hormone is in relation to the reference.

Why apply diagnostic criteria? A single hormone level does not give enough information about the TSH-FT4-FT3 relationships of the people in that level or quartile. Categorizing them as hypo- or hyperthyroid or as “nonthyroidal illness” gives information vital to interpretation in a real clinical context where these standard diagnostic categories are in use.

Why add FT3:FT4 ratio? The FT3:FT4 ratio in circulation is a net product not only of T3 and T4 secretion from the thyroid gland but also of T4-T3 conversion rates throughout the body as thyroid hormones are transported into cells and out of them again at an equal rate over time.

Why analyze further? Anderson’s article was not written for the purpose of analyzing more than the atrial fibrillation data set. Therefore, I have provided some commentary under each disorder’s table, with citations.

1) FT4, TSH and FT3 as percent of reference range.

A simple 2-step formula turns the hormone concentration’s average into a percentage of reference.

1) Subtract the lower reference limit from the FT4, TSH, or FT3 result.

2) Divide the remainder by the reference range width.

For example: TSH 0.23 within the range (0.54 – 6.80) is computed as (0.23 – 0.54) / (6.80 – 0.54) = -5% of reference. This means the value is at 5 percent of the range’s width, below the bottom of the range.

I’ve created horizontal bar graphs within each cell using the Microsoft Excel “conditional formatting” feature.

2) Diagnostic criteria

2.1 Hypothyroidism

I applied the diagnostic criteria that Garber et al, 2012 recommend for subclinical and overt hypothyroidism in the ATA/AACE guidelines:

  • “Subclinical hypothyroidism is characterized by a serum TSH above the upper reference limit in combination with a normal free thyroxine (T4).”
  • “An elevated TSH, usually above 10 mIU/L in combination with a subnormal free T4 characterizes overt hypothyroidism.”

2.2 Hyperthyroidism

Ross et al, 2016’s ATA guidelines were the authoritative source of traditional hyperthyroidism definitions:

  • “Subclinical hyperthyroidism is defined as a low or undetectable serum TSH with values within the normal reference range for both T3 and free T4.”
  • “Overt hyperthyroidism is defined as a subnormal (usually undetectable) serum thyrotropin (TSH) with elevated serum levels of triiodothyronine (T3) and/or free thyroxine estimates (free T4).”

2.3 Nonthryoidal illness (NTIS)

The definition of “nonthyroidal illness” (NTIS), also called “Low T3 syndrome,” is defined by Van den Berghe’s 2014 review on Non-Thyroidal Illness in the ICU:

  • “low or low-normal plasma thyroxine (T4), low plasma triiodothyronine (T3), increased plasma reverse T3 (rT3) concentrations, in the absence of a rise in thyrotropin (TSH).” In other words, TSH normal, FT3 low, and FT4 low or normal.

This diagnostic category has been incorrectly and prejudicially separated from hypothyroidism because of gland-centric and TSH-centric paradigms in thyroid science. It is nevertheless a state of tissue hypothyroidism in its truest sense, indicating a deficiency of the most essential thyroid hormone (T3) in circulation. The data set verifies that Low FT3 is often the most associated with illness, more so than even classically defined hypothyroidism.

The powerful metabolic inversion of healthy TSH-FT3-FT4 relationships is often misunderstood as benign or controversial. This is because it has an “Acute” phase that is not necessarily pathological, and a “Chronic” phase that indicates a failure of TSH-driven thyroidal secretion necessary to achieve recovery.

Therefore, NTIS can be either an effect or cause of illness. Low FT3 is not only caused by severe illnesses, but Low T3 can subsequently maintain and worsen illness and increase mortality rates (see “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.” In other words, in the short term, it can be a benign and temporary biochemical side-effect, but in the long term, it is a pathological metabolic derangement.

2.4 Euthyroidism

Unless otherwise specified as hypo-, hyper-, or nonthyroidal illness, a diagnosis is assumed to be euthyroid. By excluding definitions 2.1, 2.2, and 2.3, above, I defined euthyroidism as

  • TSH, FT4 and FT3 all within their reference ranges.

3) FT3:FT4 Ratio

A higher TSH usually enhances the T3 side of the FT3:FT4 ratio.

  • When TSH does not enhance the FT3:FT4 ratio, something is amiss with TSH hormone quality, TSH signaling pathways, deiodinase function, or thyroid gland function.
  • When the FT3:FT4 ratio escalates out of control without at least high-normal TSH, one should suspect TSH-receptor stimulating antibodies (Graves’ hyperthyroidism), and antibodies.

The healthy adult population has an average FT3:FT4 ratio of

  • 0.32 pmol/L (Gullo et al, 2011) (see below)
  • 0.33 pmol/L (Strich et al, 2016) age 20 and over.

Common medical myths circulate that FT3 varies too much to be reliable or that assays cannot be trusted for diagnostic purposes. Both accusations are false.

  • According to an international body that assessed standardization of thyroid hormone assays, both FT3 and FT4 assays are about equal in reliability and precision; the manufacturers have not yet calibrated them to the gold standard LCMS method. (Thienpont et al, 2010)
  • The wide circadian rhythms of TSH can interfere with diagnosis more than the narrow daily rhythm for FT3, which rises mildly at night as we sleep (See our review article “Circadian rhythms of TSH, Free T4 and Free T3 in thyroid health“).

Thyroidal T3:T4 secretion ratios as well as rates vary widely among healthy individuals, enabling them to maintain steady optimal FT3 levels and FT3:FT4 ratios in blood day to day, week to week, and month to month despite moderate metabolic challenges (See tables and data in “Thyroid T3 secretion compensates for T4-T3 conversion“).

The healthy human body regulates its FT3:FT4 ratio along with its levels of FT3 and FT4 within a very narrow band within the reference range; one person’s “optimal” location in reference will be very different from another’s. (See data in the post “Individual thyroid ranges are far narrower than lab ranges“).

How: The FT3:FT4 ratio was given a reference range and population average in Gullo et al, 2011 in pmol/L, where the 3,800+ untreated healthy controls were contrasted with 1,800+ treated patients.

In Gullo’s study, “Clinically euthyroid subjects with serum TSH<0.4 or >4.0 mU/L were excluded under suspicion of subclinical hyper- or hypothyroidism. Subjects positive for anti-TPO and/or anti-Tg antibodies and/or with hyperechogenicity or pseudo-nodular pattern at thyroid ultrasound examination were also excluded. As for athyreotic patients, also subjects in this group were subdivided by gender (F = 3,224, M = 651) and age (2,927<60 y and 948≥60 y). None of these control subjects had ever been treated with thyroid hormones or antithyroid drugs.”

Gullo’s healthy controls’ mean was 0.32 (IQR 0.27–0.37) pmol/L in a reference range from 0.20 to 0.50 pmol/L, while the LT4-treated patients had a lower ratio represented by the skewed standard deviation curve.

In Gullo’s Table 2, the TSH reference range was divided into 5 levels. At every level, the controls’ FT3:FT4 ratio was 0.31 to 0.33 pmol/L.

Anderson’s data was converted to pmol/L before dividing the average FT3 by the FT4 to enable comparison to Gullo’s FT3:FT4 reference range.

The American Medical Association (AMA) conversion calculator provides the conversion factors:

  • Free thyroxine (FT4) Result in ng/dL x 12.871 = result in pmol/L
  • Free triiodothyronine (FT3) result in pg/mL x 0.0154 = result in pmol/L

4) Analysis in light of additional scientific literature

No attempt was made to conduct a thorough or systematic literature review given the constraints of a short article. Here, I focused on literature that could comment on the specific disorder in light of FT3-FT4-TSH relationships and occasionally other relevant factors such as thyroid antibodies. I attempt to remind readers that the treated thyroid patient often has a thyroid-disorder-induced shift and a treatment-induced shift in their hormone relationships.


Click to reveal reference list

Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641.

Anderson, J. L., Jacobs, V., May, H. T., Bair, T. L., Benowitz, B. A., Lappe, D. L., Muhlestein, J. B., Knowlton, K. U., & Bunch, T. J. (2020). Free thyroxine within the normal reference range predicts risk of atrial fibrillation. Journal of Cardiovascular Electrophysiology, 31(1), 18–29.

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Categories: Cardiovascular, Chronic diseases, Health conditions, Low T3 Syndrome / NTIS, Research Reviews, Thyrotoxicosis, Tissue hypothyroidism

9 replies

  1. Wow, you have done amazing work analyzing the Anderson study! This puts even more weight on the need for a paradigm shift in treatments. It is nice to see these associations in thyroid healthy people, but I hope to see some more studies like this one which would include supplemental T4 & T3 treated subjects each categorized with their DIO mutation profiles or some other measure of the leftover T4 conversion ability.

    I especially liked the way you presented the data for the top 10 chronic diseases. I will bring this to the attention of my endocrinologist when it’s time to negotiate my next T3 raise!

    • Thanks Julien! It was a lot of work, and it helped me learn more. I agree, we need more studies of treated thyroid patients, and a full diversity of patients and treatments — each subtype needs its own analysis.


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